Potential of integrin receptors to serve as therapeutic targets for metastasized prostate cancer resistant to taxanes and androgen receptor signaling inhibitors

前列腺癌是德国男性中最普遍的实体恶性肿瘤，如果存在转移，直到世纪初，其治疗一直仅以前列腺癌为导向。在过去的十年中，系统性播散性肿瘤的治疗设备已大大扩展。最近，紫杉烷多西他赛和雄激素受体信号传导抑制剂阿比特龙都已证明，在治疗过程早期伴随雄激素剥夺开始时（即，在对紫杉醇敏感的转移性疾病中）使用时，总生存期具有优势。对于去势抵抗性转移性癌症，许多免疫和细胞毒性药物以及放射性核素和雄激素受体信号传导抑制剂已获得批准，可提供少于5个月的生存获益。不幸的是，尽管取得了这些进展，但转移性前列腺癌仍然无法治愈。特别是由于一线治疗期间的获得性耐药性，后续治疗线的药物疗效降低。为了保证长期有效的治疗反应和抵抗不期望的耐药性发展，存在对优化当前治疗方案的未满足的需求。整合素是参与调节细胞-细胞-和细胞-基质粘附的基本表面受体。它们参与控制基本的生物学过程，例如细胞增殖和分化、凋亡，特别是作为转移级联的关键步骤的迁移和侵袭。由于在耐药期间观察到几种整合素亚型的过表达和整合素触发的肿瘤细胞运动性增强，因此它们的特异性阻断可能代表了转移性前列腺癌的创新治疗选择，目前项目的主要重点是分析整合素受体在治疗耐药阶段的潜在治疗价值紫杉烷类、多西他赛和卡巴他赛以及雄激素受体信号传导抑制剂阿比特龙和恩杂鲁胺。我们打算建立对上述药物具有抗性的去势敏感性和去势抵抗性前列腺癌细胞系，并评估整合素表达谱的后续修饰。在评价细胞培养物中抗性下整联蛋白修饰的功能相关性后，将在体内原位动物模型中验证结果。最后，我们的目标是确定整合素亚型，这可能作为治疗靶点的转移性前列腺癌耐紫杉烷类和雄激素受体信号抑制剂。

Prostate cancer is the most prevalent solid malignancy in German males, which treatment, if metastasis was present, has been solely symptom-oriented till the beginning of the 21st century. During the last decade, therapeutic armamentarium for systemically disseminated tumor has been considerably expanded. Most recently, both taxane docetaxel and androgen receptor signaling inhibitor abiraterone have demonstrated an advantage in overall survival when used early in treatment course concomitantly with the beginning of androgen deprivation, i.e. in hormone-sensitive metastatic disease. For castration-resistant metastatic cancer, a number of immunologic and cytotoxic agents as well as radionucleids and androgen receptor signaling inhibitors have been approved providing a survival benefit of less than 5 months. Unfortunately, metastasized prostate cancer remains incurable despite these advances. Particularly due to acquired resistance during the first-line treatment, drug efficacy decreases in subsequent therapy lines. In order to warrant a long-term adequate therapy response and counteract undesired development of resistance, unmet need exists for optimization of the current therapeutic protocols.Protein family of integrines represents a promising therapeutic target in this context. Integrins are elementary surface receptors involved in regulation of cell-cell- and cell-matrix adhesion. They participate in controlling of essential biological processes e.g. cell proliferation and differentiation, apoptosis and specifically migration and invasion as the key steps of metastatic cascade. Since overexpression of several integrin subtypes and augmented integrin-triggered tumor cell motility has been observed during resistance, their specific blockade might represent an innovative therapeutic option for metastasized prostate cancer, particularly regarding development of resistance to currently approved agents.The main focus of the current project is directed towards analysis of the potential therapeutic value of integrine receptors in the stage of treatment resistance to taxanes docetaxel and cabazitaxel as well as androgen receptor signaling inhibitors abiraterone and enzalutamide. We intend to establish hormone-sensitive and castration-resistant prostate cancer cell lines resistant to the aforementioned drugs and assess consequent modifications of the integrine expression profile. After evaluation of the functional relevancy of integrin modifications under resistance in cell culture, the findings will be validated in an in-vivo orthotopic animal model. Finally, we aim at identification of integrin-subtypes which might serve as therapeutic targets for metastasized prostate cancer resistant to taxanes and androgen receptor signaling inhibitors.